On March 20th the New York Times1 (NYT) reported on a study in BMC Emergency Medicine (http://www.biomedcentral.com/1471-227X/12/3/abstract) that use of tranexamic acid (TXA) in trauma patients could save up to 128,000 lives annually worldwide, 4,000 of them in the United States. Yet U.S. hospitals have been slow to adopt the use of TXA in trauma patients. The issue is not cost; TXA is quite inexpensive, averaging much less than $100 per treatment in most U.S. hospitals. And the issue isn’t that the drug lacks efficacy or is unsafe since safety and efficacy have been shown in the CRASH -2 trial2.
The CRASH-2 trial published in 2010 was a remarkable achievement enrolling 20,000 patients in a randomized, placebo controlled study involving hospitals in 40 countries2. The results showed a significant reduction in death due to bleeding and a reduction in overall mortality with no increase in vascular occlusive events. Trauma patients were treated on arrival to the emergency department with a loading dose of 1 gram of TXA followed by infusion of 1 gram over 8 hours. Only patients treated within 3 hours of injury appeared to benefit, however, with those treated earliest benefiting most: a 32% reduction in death due to bleeding when TXA is given within one hour of injury (suggesting that the best time to give TXA may actually be before arrival at the hospital during transport)3.
TXA is a lysine analogue, similar in its mode of action to aminocaproic acid (Amicar) an anti-fibrinolytic drug more familiar than TXA to U.S. physicians. Both drugs are competitive inhibitors of plasminogen, binding to lysine-binding sites and preventing plasminogen activation to plasmin. However, TXA is ten times more potent than aminocaproic acid. Its value is not restricted to trauma patients. It has been shown to decrease bleeding in a variety of clinical settings. In a meta-analysis of randomized and large matched observational studies, TXA was shown to decrease bleeding, rates of re-operation, and transfusion in cardiac surgery4. TXA reduces perioperative blood loss by 25-30% in adult patients having spinal fusion surgery and up to 42% in spinal fusions in pediatric patients with neuromuscular scoliosis5, 6. Multiple studies have shown reductions in bleeding and transfusion in hip and knee arthroplasty when TXA is used7, 8. A recent systematic review and meta-analysis of the effect of TXA on surgical bleeding and transfusion concluded “the evidence…suggests that the uncertainty about the effect of tranexamic acid on blood transfusion in surgical patients was resolved over a decade ago.” Tranexamic acid reduces blood transfusion in surgical patients by about one-third across the 129 trials and 10,488 patients evaluated9.
Which brings us back to my original question: Why are U.S. hospitals so slow to adopt an inexpensive drug with proven efficacy and a good safety profile? The answer is not specific to TXA; rather the adoption rate of new medical knowledge is historically slow. In a 2003 report, the Institute of Medicine found that the lag time between significant discovery and adoption into routine care averages 17 years. This lag time has actually decreased over the last 200 years, but the challenge has also increased as the pace of medical discovery has accelerated. Research librarians estimate that a physician would need 21 hours of individual study daily just to remain current10. The “cost of change’ in terms of money, time and perceived loss of individual (physician) autonomy present significant barriers to translation from research to standard-of-care. In the case of TXA, fear of drug side effects may also be contributing to a delay in implementation (while the well-documented adverse consequences of transfusion are too often ignored).
We encourage the use of TXA to reduce transfusions. It should be adopted as part of routine management of trauma patients with hemorrhage. It should be considered as part of any comprehensive strategy to avoid transfusion in surgery with the potential for significant blood loss. What can those of us interested in patient blood management and reducing blood loss do to help educate our colleagues on the role of tranexamic acid in both trauma and elective surgery?
1) McNeil, DG (http://www.nytimes.com/2012/03/21/health/tranexamic-acid-cheap-drug-is-found-to-staunch-bleeding.html)
2) CRASH -2 Trial Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomized, placebo-controlled trial. Published on-line DOI:101016/S0140-6736(10)60835-5
3) Gruen RL. Tranexamic acid for trauma. Lancet 2011;377:1052-1054
4) Ngaage DL and Bland JM. Lessons from aprotinin: is the routine use and inconsistent dosing of tranexamic acid prudent? Meta-analysis of randomized and large matched observational studies. European Journal of Cardio-thoracic surgery 37 (2010): 1375-1383.
5) Wong J et al. Tranexamic Acid Reduces Perioperative Blood Loss in Adult Patients Having Spinal Fusion Surgery. Anesth Analg 2008;107:1479-86
6) Shapiro F, et al. Tranexamic Acid Diminishes Intraoperative Blood Loss and Transfusion in Spinal Fusions for Duchenne Muscular Dystrophy Scoliosis. Spine 2007; 32:2278-2283.
7) Johansson T, et al. Tranexamic acid in total hip arthroplasty saves blood and money: a randomized, double blind study in 100 patients. Acta Orthop. 2005;76:314-319.
8) Lozano M, et al. Effectiveness and safety of tranexamic acid administration during total knee arthroplasty. Vox Sang. 2008; 95:39-44
9) Ker et al. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ 2012;344:e3054doi: 10.1136/bmj.e3054 (Published 21 May 012)
10) Alper BS, et al. How much effort is needed to keep up with the literature relevant for primary care? J Med Libr Assoc 2004; 92(4):429-437.